EP2990416B1 - Récepteur d'antigène chimérique universel exprimant des cellules immunitaires pour le ciblage de divers antigènes multiples et son procédé de fabrication et son utilisation pour le traitement du cancer, des infections et des troubles auto-immuns - Google Patents

Récepteur d'antigène chimérique universel exprimant des cellules immunitaires pour le ciblage de divers antigènes multiples et son procédé de fabrication et son utilisation pour le traitement du cancer, des infections et des troubles auto-immuns Download PDF

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EP2990416B1
EP2990416B1 EP14182945.7A EP14182945A EP2990416B1 EP 2990416 B1 EP2990416 B1 EP 2990416B1 EP 14182945 A EP14182945 A EP 14182945A EP 2990416 B1 EP2990416 B1 EP 2990416B1
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Prior art keywords
cell
domain
antigen
cells
binding
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EP2990416A1 (fr
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Michael Bachmann
Armin Ehninger
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Avencell Europe GmbH
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Gemoab Monoclonals GmbH
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Priority to EP14182945.7A priority Critical patent/EP2990416B1/fr
Application filed by Gemoab Monoclonals GmbH filed Critical Gemoab Monoclonals GmbH
Priority to ES14182945.7T priority patent/ES2688035T3/es
Priority to PCT/EP2015/069527 priority patent/WO2016030414A1/fr
Priority to CN202210415817.XA priority patent/CN114774444A/zh
Priority to JP2017530422A priority patent/JP7215825B2/ja
Priority to EP15756392.5A priority patent/EP3186275A1/fr
Priority to AU2015308499A priority patent/AU2015308499B2/en
Priority to US15/504,012 priority patent/US10611814B2/en
Priority to CN201580043322.7A priority patent/CN106574272B/zh
Priority to CA2953276A priority patent/CA2953276C/fr
Priority to CN202110933891.6A priority patent/CN114085855A/zh
Publication of EP2990416A1 publication Critical patent/EP2990416A1/fr
Priority to HK16103488.5A priority patent/HK1215583A1/zh
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Publication of EP2990416B1 publication Critical patent/EP2990416B1/fr
Priority to US16/513,672 priority patent/US10766943B2/en
Priority to AU2020200751A priority patent/AU2020200751B2/en
Priority to US16/798,255 priority patent/US20210206828A9/en
Priority to JP2021012313A priority patent/JP2021072831A/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/7051—T-cell receptor (TcR)-CD3 complex
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/463—Cellular immunotherapy characterised by recombinant expression
    • A61K39/4631—Chimeric Antigen Receptors [CAR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
    • A61K2239/48—Blood cells, e.g. leukemia or lymphoma
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/02—Fusion polypeptide containing a localisation/targetting motif containing a signal sequence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies

Definitions

  • the present invention relates to immune cell-based therapeutics and methods of using the therapeutics in the treatment of cancer, infections and autoimmune disorders.
  • Chimeric antigen receptors are artificial receptors consisting of a binding moiety which provides the antigen-specificity and one or several signaling chains derived from immune receptors ( Cartellieri et al., J.Biomed.Biotechnol. doi: 10.1155/2010/956304 (2010 )). These two principal CAR domains are connected by a linking peptide chain including a transmembrane domain, which anchors the CAR in the cellular plasma membrane.
  • Immune cells in particular T and NK lymphocytes, can be genetically modified to express CARs inserted into their plasma membrane.
  • CAR modified immune cell encounters other cells or tissue structures expressing or being decorated with the appropriate target of the CAR binding moiety, upon binding of the CAR binding moiety to the target antigen the CAR modified immune cell is crosslinked to the target.
  • Cross-linking leads to an induction of signal pathways via the CAR signaling chains, which will change the biologic properties of the CAR engrafted immune cell.
  • CAR triggering in effector CD4+ and CD8+ T cells will activate typical effector functions like secretion of lytic compounds and cytokines which will eventually lead to the killing of the respective target cell.
  • CARs chimeric antigen receptors
  • WO 2013074916 A1 describes genetically modified T cells, which carry a chimeric antigen receptor (CAR) and which have been manipulated to impair their T cell receptor or human leukocyte antigen function.
  • the antigen binding domain of the CAR T cell is directed towards a tumor-associated antigen.
  • WO 2013126712 A1 describes genetically modified T cells, which carry a chimeric antigen receptor (CAR) whose antigen binding mediates a direct interaction with a tumor cell.
  • CAR chimeric antigen receptor
  • Arndt et al. (Leukemia (2014), 28, 59-69 ) describes a modular targeting system, consisting of a target cell binding moiety and a separate effector cell binding moiety. Both components are connected via an scFv-epitope interaction.
  • the epitope is derived from the human La protein.
  • WO 2012082841 A2 discloses universal anti-tag chimeric antigen receptor-expressing T cells and methods of treating cell related disorders, e.g. cancer.
  • WO 2013044225 A1 discloses a universal immune receptor expressed byT cells for the targeting of diverse and multiple antigens.
  • T cells expressing universal anti-tag immune receptors. These T cells can be redirected to disease-related cell surface antigens by additionally applying modules binding these surface antigens and carrying the respective tag.
  • the problem arising from the aforesaid methods is that a redirection of the genetically modified T cells using exogenous tags is likely to be immunogenic, which will put patients in danger and negatively affect efficacy of treatment. Therefore, it is an object of the present invention to provide a genetically modified immune cell that allows a redirection against diverse disorders in a safe and efficient manner using endogenous tags based on nuclear proteins. It is a further object of the present invention to provide a method of treatment of diverse cell related disorders, wherein the length and intensity of treatment is adjustable in a simple manner.
  • the present invention provides an universal, modular, anti-tag chimeric antigen receptor (UniCAR) system that allows a retargeting of UniCAR engrafted immune cells against multiple antigens.
  • the system uses a gene therapy platform to generate immune cells capable of recognizing various antigens and that have broad and valuable clinical implications for the use of immune cell-based therapies, in particular T- and NK-cell based therapies.
  • the present invention provides an isolated nucleic acid sequence encoding a universal chimeric antigen receptor, wherein the receptor comprises three domains, wherein the first domain is a tag-binding domain, the second domain is a linking peptide chain including an extracellular hinge and a transmembrane domain and the third domain is a signal transduction domain, wherein the tag-binding domain binds to a tag derived from any human nuclear protein, wherein the tag is a short linear epitope from the human nuclear La protein (E5B9) and wherein the tag-binding domain is an antibody or an antibody-derived antigen-binding fragment thereof and wherein the tag-binding domain is binding to the respective La epitope (5B9).
  • E5B9 short linear epitope from the human nuclear La protein
  • the tag-binding domain is an antibody or an antibody-derived antigen-binding fragment thereof and wherein the tag-binding domain is binding to the respective La epitope (5B9).
  • tags are peptide sequences from nuclear antigens, which cannot be accessed and bound by the corresponding tag-binding domain in the context of the native protein under physiological conditions.
  • the peptide sequence should not be the target of autoantibodies in autoimmune patients, thus making it unlikely that the tag is immunogenic in the context of the universal chimeric receptor.
  • An optional fourth domain is a short peptide linker in the extracellular portion of UniCARs, which forms a linear epitope for a monoclonal antibody (mab) specifically binding to the fourth domain. This additional domain is not required for functionality of the UniCAR system, but may add additional clinical benefit to the invention.
  • the present invention provides an isolated nucleic acid sequence encoding a universal chimeric antigen receptor according to the present invention, wherein the nucleic acid sequence encodes for an artificial chimeric fusion protein and wherein the nucleic acid sequence is provided as cDNA.
  • the present invention provides a target module for use in a method for stimulating a universal chimeric antigen receptor mediated immune response in a mammal composed of a binding moiety specific for a certain human cell surface protein or protein complex and a tag, wherein the tag is a short linear epitope from the human nuclear La protein (E5B9).
  • the present invention provides a nucleic acid encoding a target module for use in a method for stimulating a universal chimeric antigen receptor mediated immune response in a mammal according to the present invention.
  • the present invention provides an isolated nucleic acid sequence encoding a target module according to the present invention, wherein the isolated nucleic is provided as cDNA.
  • the present invention provides a cell comprising a nucleic acid encoding an universal chimeric antigen receptor according to the present invention comprising three domains, wherein the first domain is a tag-binding domain, the second domain is a linking peptide chain including an extracellular hinge and a transmembrane domain and the third domain is a signal transduction domain and wherein the tag-binding domain binds to the short linear epitope E5B9 of the human nuclear La protein.
  • the present invention provides a vector comprising a nucleic acid encoding a universal chimeric antigen receptor according to the present invention, wherein the universal chimeric antigen receptor comprises three domains, wherein the first domain is a tag-binding domain, the second domain is a linking peptide chain including an extracellular hinge and a transmembrane domain and the third domain is a signal transduction domain, wherein the tag-binding domain binds to the short linear epitope E5B9 of the human nuclear La protein.
  • the present invention provides a kit comprising a vector according to the present invention comprising a nucleic acid sequence encoding a universal chimeric antigen receptor according to the present invention and a target module as defined above and/or a vector encoding an isolated nucleic acid sequence encoding a target module as defined above.
  • a pharmaceutical composition that contains cells according to the invention and target modules as described herein in association with a pharmaceutically acceptable dilution agent or carrier.
  • the pharmaceutical composition is present in a form suitable for intravenous administration.
  • the composition comprises cells comrprising a nucleic acid encoding a universal chimeric antigen receptor according to the present invention and target modules as described herein.
  • the pharmaceutical composition comprises various administration forms.
  • the pharmaceutical compositions are preferably administered parenterally, particularly preferred intravenously.
  • the parenteral pharmaceutical composition may exist in an administration form that is suitable for injection.
  • Particularly preferred compositions are therefore solutions, emulsions, or suspensions of the cell and target module that are present in a pharmaceutically acceptable dilution agent or carrier.
  • compositions As a carrier, preferably water, buffered water, 0.4 % saline solution, 0.3 % glycine and similar solvents are used.
  • the solutions are sterile.
  • the pharmaceutical compositions are sterilized by conventional well-known techniques.
  • the compositions contain preferably pharmaceutically acceptable excipients, for example, those that are required in order to provide approximately physiological conditions and/or to increase the stability of the antibody, such as agents for adjusting the pH value and buffering agents, agents for adjusting the toxicity and the like, preferably selected from sodium acetate, sodium chloride, potassium chloride, calcium chloride and sodium lactate.
  • concentrations of the antibodies according to the invention in these formulations are variable; they are preferably less than 0.01 % by weight, preferably at least 0.1 % by weight, further preferred between 1 and 5 % by weight and they are selected primarily on the basis of fluid volumes, viscosity etc. or in compliance with the respective administration mode.
  • compositions must be sterile and stable under the manufacturing and storage conditions.
  • the composition can be formulated as a solution, microemulsion, dispersion, in liposomes or in other ordered structures that are suitable for this purpose and know by the artesian.
  • the cells of the invention and the target module are preferably introduced into a composition that is suitable for parenteral administration.
  • the pharmaceutical composition is an injectable buffered solution that contains between 0.1 to 500 mg/ml of antibody, especially preferred between 0.1 to 250 mg/ml of antibody, in particular together with 1 to 500 mmol/l (mM) of a buffer.
  • the injectable solution can be present in liquid form.
  • the buffer can be preferably histidine (preferably 1 to 50 mM, especially preferred 5 to 10 mM) at a pH value of 5.0 to 7.0 (especially preferred at a pH of 6.0).
  • Suitable buffers encompass, but are explicitly not limited to, sodium succinate, sodium citrate, sodium phosphate, or potassium phosphate.
  • sodium chloride between 0 to 300 mM, especially preferred 150 mM, is used for a liquid administration form.
  • stabilizers are preferably used, especially preferred between 1 to 50 mM of L-methionine (preferably between 5 and 10 mM).
  • the pharmaceutical composition comprises the antibody in a dosage quantity of 0.1 mg/kg to 10 mg/kg per administration. Especially preferred dosage quantities comprise 1 mg/kg of body weight.
  • the invention provides the cells according to the present invention comprising a nucleic acid encoding a universal chimeric antigen receptor according to the present invention and target modules for use in a method for stimulating a universal chimeric antigen receptor mediated immune response in a mammal.
  • the invention provides the cells according to the present invention comprising a nucleic acid encoding a universal chimeric antigen receptor according to the present invention and target modules as described herein for use as a medication, more preferably as a medication for treatment of cancer or an autoimmune disease.
  • An autoimmune disease arises from an abnormal immune response of the body against substances and tissues normally present in the body (autoimmunity).
  • the use of the cells of the invention and the target modules for preparing a medication for therapeutic and/or diagnostic use in case of cancer or an autoimmune disease.
  • a method for treatment of a human having cancer or an autoimmune disease by administration of the cells of the invention and the target modules is also described.
  • a sterile pharmaceutical composition, containing a pharmacologically effective quantity of the cells of the invention and the target module is administered to a patient in order to treat the aforementioned illnesses.
  • effector cells used in the methods of the present invention may be autologous, syngeneic or allogeneic, with the selection dependent on the disease to be treated and the means available to do so.
  • Suitable populations of effector cells that may be used in the methods include any immune cells with cytolytic, phagocytic or immunosuppressive activity, such as T cells, including regulatory T cells, NK cells and macrophages.
  • effector cells are from a certain HLA background and utilized in an autologous or allogeneic system. Effector cells can be isolated from any source, including from a tumor explant of the subject being treated or intratumoral cells of the subject being treated.
  • effector cell refers to any kind of aforementioned immune cells genetically altered to express UniCARs on their cell surface.
  • the UniCAR expressed by effector cells used in the methods of the present invention allows for a modular, highly flexible and tightly controllable retargeting of UniCAR expressing immune cells in an antigen-specific manner.
  • the sole requirements for the UniCARs used in the methods are (i) that the UniCAR has binding specificity for a particular tag that can be conjugated to a target module, which in turn binds to a cellular surface protein or an extracellular structure, and (ii) that immune cells can be engineered to express the UniCAR.
  • the UniCAR comprises three domains ( Fig. 1 ).
  • the first domain is the tag-binding domain. This domain is typically present at the amino terminal end of the polypeptide that comprises the UniCAR. Locating the tag-binding domain at the amino terminus permits the tag-binding domain unhampered access to the tagged target module that is bound to the target cell.
  • the tag-binding domain is typically, but not restricted to, an antibody or an antigen-binding fragment thereof. The identity of the antibody or fragment is only limited by the identity of the tag of the tagged target module.
  • the tag is a short linear epitope from the human nuclear La protein (E5B9).
  • the antibody may be obtained from any species of animal, though preferably from a mammal such as human, simian, mouse, rat, rabbit, guinea pig, horse, cow, sheep, goat, pig, dog or cat. Preferably the antibodies are human or humanized antibodies. Nor is there a limitation on the particular class of antibody that may be used, including IgGI, IgG2, IgG3, IgG4, IgM, IgAI, IgA2, IgD and IgE antibodies.
  • Antibody fragments include single-chain variable fragment (scFv), single chain antibodies, F(ab')2 fragments, Fab fragments, and fragments produced by a Fab expression library, with the only limitation being that the antibody fragments retain the ability to bind the selected tag.
  • the antibodies may also be polyclonal, monoclonal, or chimeric antibodies, such as where an antigen binding region (e.g., F(ab')2 or hypervariable region) of a non-human antibody is transferred into the framework of a human antibody by recombinant DNA techniques to produce a substantially human molecule.
  • Antigen-binding fragments such as scFv, may be prepared therefrom.
  • Antibodies to a selected tag may be produced by immunization of various hosts including, but not limited to, goats, rabbits, rats, mice, humans, through injection with a particular protein or any portion, fragment or oligopeptide that retains immunogenic properties of the protein.
  • adjuvants can be used to increase the immunological response.
  • adjuvants include, but are not limited to, detoxified heat labile toxin from E. coli, Freund's, mineral gels such as aluminum hydroxide, and surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin, and dinitrophenol.
  • BCG Bacillus Calmette-Guerin
  • Corynebacterium parvum are also potentially useful adjuvants.
  • Antibodies and fragments thereof can be prepared using any technique that provides for the production of antibody molecules, such as by continuous cell lines in culture for monoclonal antibody production.
  • Such techniques include, but are not limited to, the hybridoma technique originally described by Koehler and Milstein (Nature 256:495-497 (1975 )), the human B-cell hybridoma technique ( Kosbor et al., Immunol Today 4:72 (1983 ); Cote et al., Proc Natl. Acad. Sci 80:2026-2030 (1983 )), and the EBV-hybridoma technique ( Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss Inc, New York N.Y., pp 77-96 (1985 )).
  • chimeric antibodies i.e., the splicing of mouse antibody genes to human antibody genes to obtain a molecule with appropriate antigen specificity and biological activity can also be used ( Morrison et al., Proc Natl. Acad. Sci 81:6851-6855 (1984 ); Neuberger et al., Nature 312:604-608 (1984 ); Takeda et al., Nature 314:452-454 (1985 )).
  • techniques described for the production of single chain antibodies can be adapted to produce tag-specific single chain antibodies.
  • the tag-binding domain is a single-chain variable fragment (scFv).
  • a scFv comprises the variable regions of the heavy (VH) and light chains (VL) of an antibody, typically linked via a short peptide of ten to about 25 amino acids.
  • the linker can either connect the N-terminus of the VH with the C-terminus of the VL, or vice versa.
  • the binding specificity of the tag-binding domain will depend on the identity of the tag that is conjugated to the protein that is used to bind target structures.
  • the tag is a short linear epitope from the human nuclear La protein (E5B9)
  • the tag-binding domain may constitute an antibody or an antibody-derived antigen-binding fragment, e.g. a single-chain fragment variable (scFv) binding to the respective La epitope (5B9).
  • scFv single-chain fragment variable
  • cytokine storms referred to variously as cytokine storms or cytokine release syndrome (CRS).
  • CRS cytokine release syndrome
  • the second domain of the UniCAR is an extracellular hinge and a transmembrane (TM) domain.
  • the hinge domain allows the UniCAR to protrude from the surface of the effector cell for optimal binding to its particular tag.
  • the TM domain anchors the UniCAR into the cell membrane of the effector cell.
  • Exemplary hinge and TM domains include, but are not limited to, the hinge and transmembrane regions of the human CD28 molecule, the CD8a chain, NK cell receptors like natural killer group 2D (NKG2D), or parts of the constant region of an antibody as well as combinations of various hinge and TM domains.
  • the third domain when present, is the signal transduction domain.
  • This domain transmits a cellular signal into the UniCAR carrying effector cell upon cross-linkage of the effector cell to a cell or extracellular structure.
  • Cross-linkage between effector and target cell is mediated and depends on the presence of (i) a target module which binds to its particular binding moiety on the target cell or target extracellular structure and carries a tag and (ii) the UniCAR expressed on the surface of the effector cell can recognize and bind to the tag included in the target module.
  • Effector cell activation includes induction of cytokines or chemokines as well as activation of cytolytic, phagocytic or suppressive activity of the effector cell.
  • Exemplary effector cell signal transduction domains include, but are not limited to, the cytoplasmic regions of CD28, CD137 (41BB), CD134 (OX40), DAP10 and CD27, which serve to enhance T cell survival and proliferation; inhibitory receptors as programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) as well as cytoplasmic regions of the CD3 chains (e.g. CD3zeta), DAP12 and Fc receptors, which induce T and NK cell activation.
  • One or more than one signal transduction domain may be included in the UniCAR, such as two, three, four or more immune cell activating or costimulatory domains.
  • the UniCAR comprises a fourth domain which is a short peptide linker in the extracellular portion of the UniCAR ( Fig. 1 ). It is required for its functionality, that this fourth domain forms a linear epitope which allows the binding of a specific monoclonal antibody with reasonable affinity.
  • One or more than one linear epitope may be included in the fourth domain and they may be located as linker in the tag-binding domain, in between the tag-binding domain and the extracellular linker or an integral part of the extracellular hinge domain.
  • UniCAR engrafted immune cells can be specifically stimulated, so that UniCAR engrafted immune cells proliferate preferentially and persist longer compared to non-engrafted immune cells either in vitro or in vivo.
  • the fourth domain may be also used to purify UniCAR engrafted immune cells from mixed cell populations. It may be also used to dampen UniCAR engrafted immune cell mediated immune response and to eliminate UniCAR engrafted immune cells in vivo.
  • a signal peptide (sometimes also referred to as signal sequence, targeting signal, or leader peptide) is put in front of the tag-binding domain at the N-terminus of the UniCAR nuclide acid sequence.
  • Signal peptides target proteins to the secretory pathway either co-translationally or post-translationally.
  • signal peptides from proteins of various species can be utilized, however preferentially leader peptides from proteins like CD28, CD8alpha, IL-2 or the heavy or light chain of antibodies of human origin are used to avoid immunogenic reactions.
  • Target modules for use in a method for stimulating a universal chimeric antigen receptor mediated immune response in a mammal are composed of a binding moiety specific for a certain human cell surface protein or protein complex and a tag, the tag is a short linear epitope E5B9 from the human nuclear La protein.
  • Target modules are administered to a subject prior to, or concurrent with, or after administration of the UniCAR-expressing effector cells.
  • UniCAR expressing effector cells may be decorated with target modules prior to the infusion into the recipient.
  • the binding moiety of target modules include, but are not limited to, antibodies or fragments thereof that bind to surface antigens like CD2, CD3, CD4, CD8, CD10, CD19, CD20, CD22, CD23, CD33, CD38, CD44, CD52, CD99, CD123, CD274 and TIM-3, members of the epidermal growth factor receptor family (erb1, erb2, erb3, erb4 and mutants thereof), members of the ephrin receptor family (EphA1-10, EphB1-6), so called prostate specific antigens (e.g. prostate stem cell antigen PSCA, prostate specific membrane antigen PSMA), embryonic antigens (e.g.
  • prostate specific antigens e.g. prostate stem cell antigen PSCA, prostate specific membrane antigen PSMA
  • embryonic antigens e.g.
  • CEA carcinoembryonic antigen
  • fetal acethylcholine receptor members of the vascular endothelia growth factor family (VEGFR 1-3), epithelia cell adhesion molecule EpCAM, alphafetoprotein AFP, members of the mucin protein family (e.g. MUC1, MUC16), follicle stimulating hormone receptor (FSHR), the human high molecular weight-melanoma-associated antigen (HMW-MAA), folate binding protein FBP, a-Folate receptor, ligands of the NKG2D receptor, members of the epithelia glycoprotein family (e.g. EGP-2, EGP-4), diasialogangliosides (e.g.
  • the binding moiety of target modules include, but are not limited to, antibodies or fragments thereof that binds to cytoplasmic or nuclear antigens like the La/SSB antigen, members of the Rho family of GTPases, members of the high mobility group proteins and others.
  • the binding moiety of a target module can be composed of the alpha and beta or the gamma and delta chains of a T cell receptor (TCR) or fragments thereof.
  • TCR-derived binding moieties recognize and bind to peptides presented by human leukocyte antigen class (HLA) I and II protein complexes.
  • HLA human leukocyte antigen class
  • HLA human leukocyte antigen class
  • the binding moiety of target modules can also comprise ligands to proteins and protein complexes, further on referred as receptors.
  • ligands may bind to, but are not limited to, cytokine receptors (e.g. IL-13 receptor), ligands of the NKG2D receptor, ligands to the EGFR family members, or auto-reactive TCRs.
  • Binding moieties of target modules may comprise single antigen specificity (monospecific), two, three or more antigen specificities (bi- and multispecific). Examples for bi- and multispecific antigen specificities include, but are not limited to, target modules binding to PSCA and PSMA antigen, CD19 and CD20 antigen, CD19, CD20, and CD22 antigen, CD33 and CD123 antigen, CD33 and CD99, CD33 and TIM-3, erb-1 and -2, PSCA and erb-2 and further combinations. Binding moieties of target modules may also comprise monovalent binding as well a bi- and multivalent binding sites.
  • bi- and multivalent targeting strategies include, but are not limited to, target modules incorporating two scFvs recognizing different epitopes of PSCA, CD19 and CD33, and ligand-scFv combinations recognizing different epitopes of the erb1 receptor.
  • Target modules may also carry additional ligands, which are not involved in the target antigen binding, further on referred to as payloads.
  • payloads may comprise, but are not limited to, costimulatory ligands or cytokines fused to the N- or C-terminus of the target module, in particular the extracellular domain of CD28, CD137 (41BB), CD134 (OX40), and CD27, as well as IL-2, IL-7, IL-12, IL-15, IL-17, and II-21, which all stimulate different kinds of immune cells.
  • Other payloads may be radionuclides or chemical compounds which induce cell death in the target and neighboring cells.
  • a method for stimulating a universal chimeric antigen receptor - mediated immune response in a mammal comprising:
  • the effector cells and target module are administered to humans.
  • immune cells may be genetically engineered to express UniCARs by various methods.
  • a polynucleotide vector encoding the UniCAR and all necessary elements to ensure its expression in the genetically engineered immune cell is transferred into the cell.
  • the transfer of the vector can be performed, but is not limited to, by electroporation or transfection of nucleid acids or the help of viral vector systems like, but not limited to, adeno-, adeno-associated, retro-, foamy- or lentiviral viral gene transfer.
  • lentiviral gene transfer may be applied for stable expression of UniCARs in immune cells by first constructing a lentiviral vector encoding for a selected UniCAR.
  • An exemplary lentiviral vector includes, but is not limited to, the vector pLVX-EF1alpha UniCAR 28/ ⁇ (Clontech, Takara Bio Group) as shown in Fig. 3 , in which the lentiviral parts of the vector are derived from the human immunodeficiency virus (HIV).
  • the MSC/IRES/ZxGreenl portion was replaced by the UniCAR construct.
  • 5' LTR 5' long terminal repeat
  • PBS primer binding site
  • ⁇ packaging signal
  • RRE Rev-response element
  • cPPT/CTS (central polypurine tract/central termination sequence
  • PEF1 ⁇ human elongation factor 1 alpha promoter
  • MCS multiple cloning site
  • IRES internal ribosorre entry site
  • ZsGreen1 human-codon-optimized
  • WPRE woodchuck hepatitis virus posttranscriptional regulatory element
  • 3' LTR 3' long terminal repeat
  • pUC origin of replication
  • Ampr ampicillin resistance gene
  • Lentiviral particles are typically produced by transient transfection of Human Embryonal Kidney (HEK) 293T (ACC 635) cells with the UniCAR encoding lentiviral vector plasmid and cotransfection with a group specific antigen (gag) and Polymerase (pol) encoding plasmid (e.g. psPAX2, addgene plasmid 12260) as depicted in Fig. 4 plus a plasmid encoding for an envelope (e.g. pMD2.G, addgene plasmid 12259) as shown in Fig. 5 . After transfection the packaging plasmid expresses Gag and Pol protein of HIV-1. Abbrevation used in Fig.
  • CMVenh CMV enhancer and promoter
  • SD splice donor
  • SA splice acceptor
  • Gag Group-specific antigen
  • Pro Precursor protein encoding the protease protein
  • Pol Protein encoding the reverse transcriptase and integrase
  • RRE rev responsive element
  • Amp ampicillin.
  • the plasmid MD2.G ( Fig. 5 ) encodes the glycoprotein of the Vesicular Stomatitis Virus (VSV-G).
  • VSV-G protein is used to lentiviral vectors to transduce a broad range of mammalian cells.
  • Lentiviral vectors can successfully pseudotype, but are not limited to, with the envelope glycoproteins (Env) of amphotropic murine leukemia virus (MLV) or the G protein of vesicular stomatitis virus (VSV-G), a modified envelope of the prototypic foamy virus (PFV) or chimeric envelope glycoprotein variants derived from gibbon ape leukemia virus (GaLV) and MLV.
  • Env envelope glycoproteins
  • MLV amphotropic murine leukemia virus
  • VSV-G G protein of vesicular stomatitis virus
  • PFV prototypic foamy virus
  • GaLV gibbon ape leukemia virus
  • MLV gibbon ape leukemia virus
  • peripheral blood mononuclear cells PBMC
  • isolated T cells can be activated with mab specific for the CD3 complex, e.g. clone OKT3 or UCHT1, either given in solution or coated to plastic cell culture dishes or magnetic beads.
  • Activation of PBMC or isolated T cells can be further enhanced by stimulating costimulatory pathways with mabs or ligands specific for, but not limited to, CD27, CD28, CD134 or CD137 either alone or in various combinations and the supply with exogenous recombinant cytokines like, but not limited to, interleukin (IL)-2, IL-7, IL-12, IL-15 and IL-21.
  • IL interleukin
  • Concentrated or non-concentrated virus particles are added to PBMC or T cell cultures 24h to 96h after initial administration of activating CD3 antibodies and/or recombinant cytokines as single or multiple doses.
  • Stable transduction of T cells may be determined flow cytometry after staining with tag-containing target modules for surface expression of UniCARs or mabs directed against the fourth domain of UniCARs from day 3 onwards after final administration of virus supernatant.
  • UniCAR transduced T cells can be propagated in vitro by culturing them under supply of recombinant cytokines and activating anti-CD3 mabs.
  • immune cells genetically modified to express UniCARs can be specifically propagated in vitro by coating a mab or antibody fragments thereof binding to the fourth UniCAR domain to the surface of culture dishes or to beads of any kind, which are added to the cell culture at a defined ratio of, but not limited to, 1 bead to 1-4 UniCAR engrafted effector cells.
  • the binding of surface-coated mabs to the UniCAR peptide domain induces cross-linkage of cell-surface expressed UniCARs and formation of an immune synapse, which leads to the activation of signal pathways specifically triggered by the signal domain of the UniCAR. Depending on the signal pathways induced, this may leads to enhance proliferation and sustained resistance against activation-induced cell death of the UniCAR carrying immune cells and therefore enrichment of UniCAR genetically modified immune cells in a mixed population.
  • the optional fourth domain a peptide sequence forming a linear epitope for a mab
  • the optional fourth domain can be further utilized to enrich and purify UniCAR expressing immune cells from mixed populations. Enrichment and purification can be performed with the help of a mab or antibody fragments thereof binding to the fourth UniCAR domain to either mark UniCAR expressing cells for cell sorting or to transiently link the UniCAR expressing immune cell to small particles, which can be utilized for cell isolation.
  • UniCAR engrafted immune cells are incubated with the mab recognizing the fourth domain.
  • magnetic beads are added, which are conjugated with antibodies or fragment's thereof directed against the species-and isotype specific heavy and light chains of the mab binding to the optional fourth domain.
  • UniCAR expressing immune cells and magnetic beads are linked and can be trapped and separated from other immune cells in a magnetic field.
  • the optional fourth domain can be used for detection of UniCAR surface expression as shown in Fig. 6.
  • Fig. 6 (A) depicts that UniCAR surface expression can be detected by using a monoclonal antibody directed against the optional 4th domain and subsequently staining with a fluorochrome-conjugated anti-species secondary antibody.
  • the optional 4th domain can be additionally used to purify UniCAR engrafted T cells to high purity as depicted in Fig. 6 ) in the
  • Populations of UniCAR-expressing immune cells may be formulated for administration to a subject using techniques known to the skilled artisan.
  • Formulations comprising populations of UniCAR-expressing immune cells may include pharmaceutically acceptable excipient(s).
  • Excipients included in the formulations will have different purposes depending, for example, on the nature of the tag-binding domain comprising the UniCARs, the population of immune cells used, and the mode of administration.
  • Examples of generally used excipients include, without limitation: saline, buffered saline, dextrose, water-for- infection, glycerol, ethanol, and combinations thereof, stabilizing agents, solubilizing agents and surfactants, buffers and preservatives, tonicity agents, bulking agents, and lubricating agents.
  • the formulations comprising populations of UniCAR-expressing immune cells will typically have been prepared and cultured in the absence of any non-human components, such as animal serum (e.g., bovine serum albumin).
  • a formulation may include one population or more than one, such as two, three, four, five, six or more populations of UniCAR-expressing immune cells.
  • the different populations of UniCAR engrafted immune cells can vary based on the identity of the tag-binding domain, the identity of the signal transduction domain, the identity of the subpopulations, the mode of generation and cultivation or a combination thereof.
  • a formulation may comprise populations of UniCAR-expressing T and NK cells that recognize and bind to one, or more than one, such as two, three, four, five, six or more different tagged proteins.
  • the formulations comprising population(s) of UniCAR immune cells may be administered to a subject using modes and techniques known to the skilled artisan.
  • Exemplary modes include, but are not limited to, intravenous injection.
  • Other modes include, without limitation, intratumoral, intradermal, subcutaneous (s.c, s.q., sub-Q, Hypo), intramuscular (i.m.), intraperitoneal (i.p.), intra-arterial, intramedulary, intracardiac, intra- articular (joint), intrasynovial (joint fluid area), intracranial, intraspinal, and intrathecal (spinal fluids).
  • Any known device useful for parenteral injection or infusion of the formulations can be used to effect such administration.
  • Injections can be performed as bulk injections or continuous flow injections.
  • the formulations comprising population(s) of UniCAR-expressing immune cells that are administered to a subject comprise a number of UniCAR-expressing immune cells that is effective for the treatment and/or prophylaxis of the specific indication or disease.
  • therapeutically-effective populations of UniCAR-expressing immune cells are administered to subjects when the methods of the present invention are practiced.
  • the number of UniCAR-expressing immune cells administered to a subject will vary between wide limits, depending upon the location, source, identity, extent and severity of the disease, the age and condition of the individual to be treated, etc. A physician will ultimately determine appropriate dosages to be used.
  • UniCAR engrafted immune cells can be depleted from an individual by the administration of a mab directed against the peptide domain (fourth domain) of the UniCAR forming a linear epitope for the respective antibody.
  • Target modules comprise two domains, a binding moiety specific for a certain human cell surface protein or protein complex and a tag, against which the tag-binding domain of the UniCAR is directed.
  • Target modules can be manufactured by techniques known to the skilled artisan. These techniques include, but are not limited to, recombinant expression in pro- or eukaryotic cells or artificial synthesis of polypeptide chains.
  • a target module may be expressed in Chinese ovarian hamster (CHO, ACC-110) cells, which are suitable for synthesizing high amount of recombinant proteins in their biologically active forms.
  • a nucleic acid sequence coding for a target module can be transferred into CHO cells by established genetically engineering techniques like, but not limited to, naked nucleic acid transfection, electroporation or viral gene transfer.
  • High productive single-cell clones may be selected from parental lines using, for example, the dihydrofolate reductase (DHFR) selection system. In this system, DHFR-deficient CHO cell mutants (e.g.
  • CHO sub-line DXB11 or DG44 are genetically modified by co-transfection of a functional copy of the DHFR gene in addition to the nucleic acid sequence coding for a target module. Clonal selection is then performed by growth in media devoid of glycine, hypoxanthine and thymidine. High-productive clones can be further selected by culturing the cells in high levels of methotrexate (MTX), a folic acid analog that blocks DHFR activity. As gene modified cells must cope with the decrease in DHFR activity, which cannot be rescued by the mere presence of a single copy of the DHFR, clones with amplified copies of the DHFR gene are favored under these conditions.
  • MTX methotrexate
  • Target modules may be isolated from cell culture supernatants by established preparative protein purification methods including preliminary steps like precipitation or ultracentrifugation and various purification techniques like, but not limited to, size exclusion or ion exchange chromatography.
  • the nucleic acid sequence of a target module carries a coding sequence for six to eight successive histidine amino acids which form a polyhistidine tag. The polyhistidine binds strongly to divalent metal ions such as nickel and cobalt.
  • Cell culture supernatant can be passed through a column containing immobilized nickel ions, which binds the polyhistidine tag, whereas all untagged proteins pass through the column.
  • the target module can be eluted with imidazole, which competes with the polyhistidine tag for binding to the column, or by a decrease in pH, which decreases the affinity of the tag for the resin.
  • One target module or more than one, like two, three, four or more target modules may be formulated for administration to a subject using techniques known to the skilled artisan.
  • Formulations containing one or more than one target module(s) may include pharmaceutically acceptable excipient(s).
  • Excipients included in the formulations will have different purposes depending, for example, on the nature of the target modules and the mode of administration. Examples of generally used excipients include, without limitation: saline, buffered saline, dextrose, water-for- infection, glycerol, ethanol, and combinations thereof, stabilizing agents, solubilizing agents and surfactants, buffers and preservatives, tonicity agents, bulking agents, and lubricating agents.
  • the formulations comprising target modules will typically have been prepared and cultured in the absence of any non-human components, such as animal serum (e.g., bovine serum albumin).
  • a formulation may include one target module or more than one, such as two, three, four, five, six or more target modules.
  • Target modules can vary based on the identity of the binding moiety, the identity of the tag, the mode of generation or a combination thereof.
  • a formulation may comprise target modules that recognize and bind to one, or more than one, such as two, three, four, five, six or more different human cell surface proteins, protein complexes or extracellular matrix structures.
  • Formulations comprising population(s) of UniCAR expressing immune cells may be incubated with a formulation including one or more target modules ex vivo, to decorate the UniCAR expressing immune cells with target modules before administration to a subject.
  • formulations including one or more target modules can be administered directly to a subject or a combination of both strategies can be chosen.
  • Route and dosage will vary between wide limits, depending upon the location, source, identity, extent and severity of the disease, the age and condition of the individual to be treated, etc. A physician will ultimately determine appropriate routes of application and dosages to be used.
  • UniCAR genetically engineered T cells can be specifically redirected against tumor cells expressing PSCA and/or PSMA as frequently detected in biopsies e.g. from prostate, bladder, pancreatic and breast tumors ( Fig. 7 ).
  • Human T cells were mock transduced (white bars) or transduced with lentiviral vectors encoding the UniCAR containing a dual CD28/CD3zeta signaling domain (black bars) or lacking any signaling domain (hatched bars) or expressing only EGFP marker protein (stripped bars).
  • PC3-PSCA prostate stem cell antigen
  • PC3-PSMA prostate membrane antigen
  • T cells were incubated at an effector to target ratio (e:t) of 5:1 or 1:1 with 51Cr-loaded PC3 target cells.
  • Target modules (TM) specific for PSCA ( ⁇ PSCA TM) or PSMA ( ⁇ PSMA TM) were added at a concentration of 15 nMol. After 20h cultivation target cell lysis (chromium release) was measured. Plots show mean and s.d. from experiments with three individual T cell donors ( Fig. 7A ).
  • Fig. 8 shows concentration-response curves for UniCAR genetically modified human T cells in the presence of target modules binding to various antigens on the surface of tumor cells of different origins.
  • Human T cells were transduced with lentiviral vectors encoding the UniCAR containing a dual CD28/CD3zeta signaling domain.
  • UniCAR engrafted T cells were incubated at an e:t ratio of 5:1 with 51Cr-loaded PC3 target cells genetically engineered to either express PSCA or PSMA antigen.
  • Target modules (TMs) specific for PSCA ( ⁇ PSCA TM) or PSMA ( ⁇ PSMA TM) were added at increasing concentrations ( Fig. 7A ).
  • Half maximal effective dosis was determined to be approximately 12 pMol for both TMs. Additional experiments were performed as in Fig. 7A , but an e:t ratio of 1:1 was chosen and the acute myeloid leukemia cell line MOLM-13 was used as target tumor cells. TMs specific either for CD33 antigen ( ⁇ CD33 TM) or CD123 antigen ( ⁇ CD123 TM) were added at increasing concentrations and EC50 values of 137 pMol for ⁇ CD33 TM and 45 pMol for ⁇ CD123 TM were determined.
  • Fig. 9 demonstrates that UniCAR engineered T cells can efficiently kill acute myeloid leukemia (AML) blasts.
  • Human T cells were mock transduced (wt, rhombs) or transduced with lentiviral vectors encoding the U-CAR containing a dual CD28/CD3zeta signaling domain (CAR 28/ ⁇ , open and closed circles) or lacking any signaling domain (CAR Stop, up-pointing triangle) or expressing only EGFP marker protein (vc, down-pointing triangle).
  • T cells were incubated with 2*10 4 Alexa eFluor 674 labeled target cells from 3 AML cell lines (MOLM-13, MV4-11, OCI-AML3) in the presence (+) or absence (-) of 0.1 nMol CD33-specific ( ⁇ CD33 TM, upper panel) or CD123-specific ( ⁇ CD123 TM, lower panel) target moduls (TM) at an e:t ratio of 1:1 for 24h ( Fig. 9A ). Number of living, propidiumiodid (PI) negative, but Alexa eFluor 674 positive target cells was determined by flow cytometry using a MACSQuant® Analyzer.
  • the number of living leukemic target cells was normalized to a control sample with target cells but without any T cells.
  • This experiment demonstrates that UniCAR engrafted T cells efficiently lyse AML blasts after cross-linkage with the corresponding TM independent of antigen density, which for CD33 is high on MOLM-13, intermediate on MV4-1,1 and low on OCI-AML3 whereas for CD123 antigen density is in the reverse order on the 3 cell lines.
  • AML blast are eliminated by UniCAR engrafted T cells upon TM mediated cross-linkage even at low e:t ratios as typically found in patient samples ( Fig. 9B ).
  • Experimental set-up was similar to Fig.
  • a low e:t ratio of 1:5 was chosen.
  • Number of living, PI negative T cells and target cells was determined by flow cytometry using a MACSQuant® Analyzer at the indicated time points. The number of living leukemic target cells was normalized to a control sample with target cells but lacking any T cells ( Fig. 9B ). Upon activation via CAR mediated signaling, UniCAR engrafted T cells start to proliferate as shown in Fig. 9C . Experimental set-up was as described for Fig. 9B and T cell numbers were determined by flow cytometry using a MACSQuant® Analyzer.
  • T cell expansion was calculated as the ratio of T cells present in samples after 144h (d6) to the number seeded at start of the experiment (d0).
  • Statistical analysis for Fig. 8A and B was performed using non-parametric one-way ANOVA (Kruskal-Wallis test) and post-hoc Dunn's Multiple Comparison test.
  • Fig. 10 shows redirection of T cells engrafted with UniCARs against two antigens simultaneously. Due to its modular nature, the UniCAR technology allows a redirection of UniCAR engrafted immune cells (e.g. T cells) against two antigens simultaneously or consecutively using either two individual TMs (TM 1 + TM 2, Fig. 10A left side), or combined bi-specific TMs (TM1-2, Fig. 10A right side) arranged as bispecific single chain tandem constructs ( Fig. 10A ).
  • T cells UniCAR engrafted immune cells
  • Using a bispecific TM targeting two antigens can be even more efficient than using a combination of two single-antigen specific TMs, as demonstrated by concentration-response curves for combined CD33- and CD123-specific retargeting of UniCAR engrafted T cells against AML cell lines ( Fig. 10B ).
  • Human T cells were transduced with a lentiviral vector encoding the UniCAR containing a dual CD28/CD3zeta signaling domain.
  • UniCAR engrafted T cells were incubated at an e:t ratio of 1:1 with Cr51-labeled MOLM-13 (mean from experiments with T cells from 4 different healthy human donors, triangles) and OCI-AML3 (mean from experiments with T cells from 2 different healthy human donors, open circles) for 24h.
  • Target modules (TM) specific for CD33 ( ⁇ CD33 TM), CD123 ( ⁇ CD123 TM) or bi-specific CD33-CD123 TM ( ⁇ CD123-CD33 TM) were added at increasing concentrations.
  • T cells were incubated with 2*10 4 Alexa eFluor 674 labeled target cells from 3 AML cell lines (MOLM-13, MV4-11, OCI-AML3) in the presence (+) or absence (-) of total amount of 100 pMol TMs at an e:t ratio of 1:5 for 144h. TMs were refreshed after 48h. Number of living, PI negative but Alexa eFluor 674 positive target cells was determined by flow cytometry using a MACSQuant® Analyzer and compared to control samples with target cells but without any T cells ( Fig. 10C , open circles).
  • T cell expansion was calculated as the ratio of T cells present in samples after 144h (d6) to the number seeded at start of the experiment (d0) in Fig. 10D . Results from experiments with 6 donors are shown, mean and s.d. are indicated.
  • UniCAR genetically modified T cells from an AML patient are enabled to attack and lyse AML cells by adding AML antigen-specific TMs.
  • Modified T cells were incubated with 2*10 4 Alexa eFluor 674 labeled target cells from 3 AML cell lines (MOLM-13, MV4-11, OCI-AML3) for 24h in the presence (+) or absence (-) of total amount of 0.5 nMol TM at an e:t ratio of 1:1. Number of living, PI negative but Alexa eFluor 674 positive target cells was determined by flow cytometry using a MACSQuant® Analyzer
  • Fig. 11 depicts diagrams showing in vivo pharmokinetics of bispecific ⁇ CD123-CD33 target module.
  • NSG mice NOD/SCID IL2Ry-/-
  • ⁇ CD123-CD33 TM either intravenously (i.v. in Fig. 11A ) or intraperitoneal (i.p. in Fig. 11B ) and serum samples were taken at indicated time points.
  • Half-time decay was determined for the i.v. injection using an exponential one phase decay model (software GraphPad Prism).
  • an isolated nucleic acid sequence encoding a universal chimeric antigen receptor according to SEQ. ID 1 is provided.
  • the product of the protein expression of the isolated nucleic acid sequence according to SEQ. ID 1 can be obtained in SEQ. ID 27.
  • the nucleic acid sequence of humanized anti-La 5B9 variable region heavy chain according to SEQ. ID 3 encodes for a protein according to SEQ. ID 33, whereas the humanized anti-La 5B9 variable region light chain according to SEQ. ID 4 encodes for a protein according to SEQ. ID 34.
  • the nucleic acid sequence of human La 7B6 epitope according to SEQ. ID 5 encodes for a protein domain according to SEQ. ID 35.
  • an isolated nucleic acid sequence encoding a target module with a binding moiety for prostate specific antigens PSCA is provided in SEQ. ID 10.
  • the product of protein expression of the nucleic acid according to SEQ. ID 10 can be obtained from SEQ. ID 28.
  • the nucleic acid sequence of the humanized light chain of an anti-PSCA scFv according to SEQ. ID 12 encodes for a protein domain according to SEQ. ID 36
  • the humanized heavy chain of an anti-PSCA scFv according to SEQ. ID 13 encodes for a protein domain according to SEQ. ID 37
  • the La 5B9 epitop according to SEQ. ID 14 encodes for a protein according to SEQ. ID 44.
  • an isolated nucleic acid sequence encoding a target module with a binding moiety for prostate specific antigens PSMA is provided in SEQ. ID 17.
  • the product of protein expression of the nucleic acid according to SEQ. ID 17 can be obtained from SEQ. ID 29.
  • the nucleic acid sequence of the humanized heavy chain of an anti-PSMA scFv according to SEQ. ID 18 encodes for a protein domain according to SEQ. ID 38
  • the humanized light chain of an anti-PSMA scFv according to SEQ. ID 19 encodes for a protein domain according to SEQ. ID 39.
  • the La 5B9 epitop according to SEQ. ID 14 encodes for a protein according to SEQ. ID 44.
  • an isolated nucleic acid sequence encoding a target module with a binding moiety for anti-CD33 antigen is provided in SEQ. ID 20.
  • the product of protein expression of the nucleic acid according to SEQ. ID 20 can be obtained from SEQ. ID 30.
  • the nucleic acid sequence of the humanized light chain of an anti-CD33 scFv according to SEQ. ID 21 encodes for a protein domain according to SEQ. ID 40
  • the humanized heavy chain of an anti-CD33 scFv according to SEQ. ID 22 encodes for a protein domain according to SEQ. ID 41.
  • the La 5B9 epitop according to SEQ. ID 14 encodes for a protein according to SEQ. ID 44.
  • an isolated nucleic acid sequence encoding a target module with a binding moiety for anti-CD123 antigen is provided in SEQ. ID 23.
  • the product of protein expression of the nucleic acid according to SEQ. ID 23 can be obtained from SEQ. ID 31.
  • the nucleic acid sequence of the humanized heavy chain of an anti-CD123 scFv according to SEQ. ID 24 encodes for a protein domain according to SEQ. ID 42
  • the humanized light chain of an anti-CD123 scFv according to SEQ. ID 25 encodes for a protein domain according to SEQ. ID 43
  • the La 5B9 epitop according to SEQ. ID 14 encodes for a protein according to SEQ. ID 44.
  • an isolated nucleic acid sequence encoding a target module with a binding moiety for anti-CD123-anti-CD33 antigen is provided in SEQ. ID 26.
  • the product of protein expression of the nucleic acid according to SEQ. ID 26 can be obtained from SEQ. ID 32.
  • the nucleic acid sequence of the humanized heavy chain of an anti-CD123 scFv according to SEQ. ID 24 encodes for a protein domain according to SEQ. ID 42
  • the humanized light chain of an anti-CD123 scFv according to SEQ. ID 25 encodes for a protein domain according to SEQ. ID 43
  • the La 5B9 epitop according to SEQ. ID 14 encodes for a protein according to SEQ. ID 44.
  • the nucleic acid sequence of the humanized heavy chain of an anti-CD33 scFv according to SEQ. ID 22 encodes for a protein domain according to SEQ. ID 41
  • the humanized light chain of an anti-CD33 scFv according to SEQ. ID 21 encodes for a protein domain according to SEQ. ID 40.

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Claims (16)

  1. Acide nucléique codant un récepteur d'antigène chimérique universel, dans lequel le récepteur comprend trois domaines, où
    - le premier domaine est un domaine de liaison au marqueur,
    - le deuxième domaine est un domaine charnière extracellulaire et un domaine transmembranaire et
    - le troisième domaine est un domaine de transduction de signal,
    dans lequel le domaine de liaison au marqueur se lie à un marquer dérivé d'une protéine nucléaire humaine, où le marquer est l'épitope linéaire court E5B9 de la protéine nucléaire humaine La et dans lequel le domaine de liaison au marqueur est un anticorps ou un fragment de liaison à l'antigène de celui-ci et dans lequel le domaine de liaison au marqueur se lie à l'épitope La 5B9 respectif.
  2. Acide nucléique selon la revendication 1, dans lequel le fragment de liaison à l'antigène est un scFv d'épitope anti-La codé par les SEQ. ID 3 et 4.
  3. Acide nucléique selon la revendication 1 ou 2, dans lequel la région charnière et transmembranaire est choisie parmi les régions charnières et transmembranaires de la molécule CD28 humaine, de la chaîne CD8a, des récepteurs des cellules NK, de préférence le groupe tueur naturel NKG2D ou des parties de la région constante d'un anticorps ainsi que des combinaisons de différents domaines charnière et transmembranaire de ceux-ci.
  4. Acide nucléique selon l'une quelconque des revendications 1 à 3, dans lequel le domaine de transduction de signal est choisi parmi les régions cytoplasmiques de CD28, CD137 (41BB), CD134 (0X40), DAP10 et CD27, la mort cellulaire programmée 1 (PD-1), l'antigène 4 des lymphocytes T cytotoxiques (CTLA-4) et les régions cytoplasmiques des chaînes CD3, l'activation des cellules DAP12 et T induisant des récepteurs Fc.
  5. Acide nucléique selon l'une quelconque des revendications 1 à 4, dans lequel le récepteur comprend un quatrième domaine qui est un segment de liaison peptidique court dans la partie extracellulaire du récepteur.
  6. Acide nucléique selon l'une quelconque des revendications 1 à 5 selon la SEQ. ID 1.
  7. Module cible utilisable dans un procédé de stimulation d'une réponse immunitaire à médiation par un récepteur d'antigène chimérique universel chez un mammifère, composé d'un fragment de liaison spécifique d'une protéine de surface cellulaire humaine ou d'un certain complexe protéique et un marquer, le marquer étant l'épitope linéaire court E5B9 de la protéine nucléaire humaine La.
  8. Module cible utilisable dans un procédé de stimulation d'une réponse immunitaire à médiation par un récepteur d'antigène chimérique universel chez un mammifère selon la revendication 7, dans lequel le fragment de liaison des modules cibles comprend des anticorps ou des fragments de ceux-ci se liant aux antigènes de surface CD2, CD3, CD4, CD8, CD10, CD19, CD20, CD22, CD23, CD33, CD38, CD44, CD52, CD99, CD123, CD274, TIM-3, des membres de la famille des récepteurs du facteur de croissance épidermique et leurs mutants, des membres de la famille des récepteurs d'éphrine, des antigènes spécifiques de la prostate PSCA ou PSMA, des antigènes embryonnaires, des membres de la famille des facteurs de croissance endothéliales vasculaires, la molécule d'adhésion de cellule épithéliale EpCAM, l'alphafétoprotéine AFP, des membres de la famille des protéines muciniques, le récepteur hormonal stimulant les follicules, l'antigène associé au mélanome humain de haute masse moléculaire, la protéine de liaison des folates FBP, le récepteur α du folate, des ligands du récepteur NKG2D, des membres de la famille des épithéliums glycoprotéiques, des disialogangliosides, des membres de la famille de l'anhydrase carbonique, des membres de la famille des antigènes carbohydrates, des membres de la famille Rho de GTPases, des membres des protéines du groupe à mobilité élevée et des mutants de ceux-ci et dans lequel le fragment de liaison des modules cibles est composé des chaînes alpha et bêta ou gamma et delta d'un récepteur de cellules T ou de fragments de ceux-ci, en particulier de récepteurs dérivés de récepteurs de cellules T auto-réactifs, dans lesquels ces fragments de liaison dérivés de récepteurs de cellules T reconnaissent et se lient aux peptides présentés par les complexes de protéines d'antigène leucocytaire humains de classe I et II.
  9. Module cible utilisable dans un procédé de stimulation d'une réponse immunitaire à médiation par un récepteur d'antigène chimérique universel chez un mammifère selon l'une quelconque des revendications 7 à 8, dans lequel le fragment de liaison des modules cibles comprend des ligands aux protéines et aux complexes protéiques qui se lient aux récepteurs de la cytokine, des ligands du récepteur NKG2D ou des ligands aux membres de la famille EGFR.
  10. Module cible utilisable dans un procédé de stimulation d'une réponse immunitaire à médiation par un récepteur d'antigène chimérique universel chez un mammifère selon l'une quelconque des revendications 7 à 9, dans lequel le fragment de liaison des modules cibles comprend des spécificités d'antigène bi et multi spécifique, y compris la liaison à l'antigène PSCA et à l'antigène PSMA, l'antigène CD19 et CD20, l'antigène CD19, CD20 et CD22, l'antigène CD33 et CD123, CD33 et CD99, CD33 et TIM-3, erb-1 et -2, PSCA et erb-2.
  11. Module cible utilisable dans un procédé de stimulation d'une réponse immunitaire à médiation par un récepteur d'antigène chimérique universel chez un mammifère selon l'une quelconque des revendications 7 à 10, dans lequel le fragment de liaison des modules cibles comprend des anticorps ou des fragments de ceux-ci qui se lient à l'antigène La, de préférence selon la SEQ. ID 28, 29, 30, 31 et 32.
  12. Acide nucléique codant pour un module cible tel que défini dans l'une quelconque des revendications 7 à 11, de préférence avec une séquence selon la SEQ. ID. 10, 17, 20, 23 et 26, utilisable dans un procédé de stimulation d'une réponse immunitaire à médiation par un récepteur d'antigène chimérique universel chez un mammifère.
  13. Cellule ou vecteur comprenant un acide nucléique selon l'une quelconque des revendications 1 à 6.
  14. Cellule selon la revendication 13, dans laquelle la cellule est choisie dans le groupe des cellules immunitaires comprenant une cellule T, une cellule tueuse naturelle, un lymphocyte T cytotoxique et une cellule T régulatrice.
  15. Kit comprenant :
    - un vecteur selon la revendication 13 et
    - un module cible tel que défini dans l'une quelconque des revendications 7 à 11 et / ou un vecteur comprenant un acide nucléique tel que défini dans la revendication 12.
  16. Cellule selon l'une quelconque des revendications 13 ou 14 et module cible tel que défini dans l'une quelconque des revendications 7 à 11 utilisables dans un procédé de stimulation d'une réponse immunitaire à médiation par un récepteur d'antigène chimérique universel chez un mammifère.
EP14182945.7A 2014-08-29 2014-08-29 Récepteur d'antigène chimérique universel exprimant des cellules immunitaires pour le ciblage de divers antigènes multiples et son procédé de fabrication et son utilisation pour le traitement du cancer, des infections et des troubles auto-immuns Active EP2990416B1 (fr)

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ES14182945.7T ES2688035T3 (es) 2014-08-29 2014-08-29 Receptor de antígeno universal que expresa células inmunes para direccionamiento de antígenos múltiples diversos, procedimiento para fabricación del mismo y utilización del mismo para tratamiento de cáncer, infecciones y enfermedades autoinmunes
EP14182945.7A EP2990416B1 (fr) 2014-08-29 2014-08-29 Récepteur d'antigène chimérique universel exprimant des cellules immunitaires pour le ciblage de divers antigènes multiples et son procédé de fabrication et son utilisation pour le traitement du cancer, des infections et des troubles auto-immuns
CA2953276A CA2953276C (fr) 2014-08-29 2015-08-26 Recepteur d'antigene chimerique universel exprimant des cellules immuno-competentes pour le ciblage de divers antigenes multiples et son procede de fabrication et son utilisation pour le traitement du cancer, des infections et des troubles auto-immuns
JP2017530422A JP7215825B2 (ja) 2014-08-29 2015-08-26 多様な多重抗原のターゲティングのための汎用的キメラ抗原受容体を発現する免疫細胞および該免疫細胞の製造方法ならびに該免疫細胞の、癌、感染症および自己免疫疾患の治療のための使用
EP15756392.5A EP3186275A1 (fr) 2014-08-29 2015-08-26 Récepteur d'antigène chimérique universel exprimant des cellules immuno-compétentes pour le ciblage de divers antigènes multiples et son procédé de fabrication et son utilisation pour le traitement du cancer, des infections et des troubles auto-immuns
AU2015308499A AU2015308499B2 (en) 2014-08-29 2015-08-26 Universal chimeric antigen receptor expressing immune cells for targeting of diverse multiple antigens and method of manufacturing the same and use of the same for treatment of cancer, infections and autoimmune disorders
US15/504,012 US10611814B2 (en) 2014-08-29 2015-08-26 Universal chimeric antigen expressing immune cells for targeting of diverse multiple antigens and method of manufacturing the same and use of the same for treatment of cancer, infections and autoimmune disorders
CN201580043322.7A CN106574272B (zh) 2014-08-29 2015-08-26 靶向多样的多种抗原的通用嵌合抗原受体表达性免疫细胞及其制造方法及其在癌症、感染和自身免疫病的治疗中的应用
PCT/EP2015/069527 WO2016030414A1 (fr) 2014-08-29 2015-08-26 Récepteur d'antigène chimérique universel exprimant des cellules immuno-compétentes pour le ciblage de divers antigènes multiples et son procédé de fabrication et son utilisation pour le traitement du cancer, des infections et des troubles auto-immuns
CN202110933891.6A CN114085855A (zh) 2014-08-29 2015-08-26 通用嵌合抗原受体表达性免疫细胞及其制造方法和治疗用途
CN202210415817.XA CN114774444A (zh) 2014-08-29 2015-08-26 通用嵌合抗原受体表达性免疫细胞及其制造方法和治疗用途
HK16103488.5A HK1215583A1 (zh) 2014-08-29 2016-03-24 靶向於不同的多種抗原的通用嵌合抗原受體表達免疫細胞及其生產方法及其用於治療癌症、感染和自身免疫障礙的用途
US16/513,672 US10766943B2 (en) 2014-08-29 2019-07-16 Universal chimeric antigen expressing immune cells for targeting of diverse multiple antigens and method of manufacturing the same and use of the same for treatment of cancer, infections and autoimmune disorders
AU2020200751A AU2020200751B2 (en) 2014-08-29 2020-01-31 Universal chimeric antigen receptor expressing immune cells for targeting of diverse multiple antigens and method of manufacturing the same and use of the same for treatment of cancer, infections and autoimmune disorders
US16/798,255 US20210206828A9 (en) 2014-08-29 2020-02-21 Universal chimeric antigen expressing immune cells for targeting of diverse multiple antigens and method of manufacturing the same and use of the same for treatment of cancer, infections and autoimmune disorders
JP2021012313A JP2021072831A (ja) 2014-08-29 2021-01-28 多様な多重抗原のターゲティングのための汎用的キメラ抗原受容体を発現する免疫細胞および該免疫細胞の製造方法ならびに該免疫細胞の、癌、感染症および自己免疫疾患の治療のための使用

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EP15756392.5A Pending EP3186275A1 (fr) 2014-08-29 2015-08-26 Récepteur d'antigène chimérique universel exprimant des cellules immuno-compétentes pour le ciblage de divers antigènes multiples et son procédé de fabrication et son utilisation pour le traitement du cancer, des infections et des troubles auto-immuns

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